HK1161967A - Substance delivering punctum implants and methods - Google Patents

Description

Substance-delivering punctal implants and methods

RELATED APPLICATIONS

This patent application claims priority from U.S. provisional patent application No. 61/139,456, filed on 19.12.2008, the entire disclosure of which is expressly incorporated herein by reference.

Technical Field

The present invention relates generally to medical devices and methods, and more particularly to implantable devices for delivering therapeutic or diagnostic substances and related methods for making and using such devices.

Disclosure of Invention

The nasolacrimal system is a series of openings and conduits that form a network of tiny drains through which tears can drain from the eye into the nasal cavity. Tears that collect on the surface of the eye flow along the edges of the eyelids toward the nose where they pass through small openings called puncta (i.e., the upper and lower puncta) and then into a conduit called the lacrimal canaliculus. Tears flow through the canaliculus into a structure known as the lacrimal sac. Tears that accumulate in the lacrimal sac then drain from the lacrimal sac into the nasal cavity through a conduit known as the nasolacrimal duct.

In adults, each punctum is about 0.3mm in diameter. The upper and lower puncta are located on the medial side of the upper and lower lid margins, respectively. Each punctum is located on top of a bulge called the papilla lachrymae.

After passing through each punctum, tear fluid flows into the initial vertical segment of the canaliculus. Such vertical segments are typically about 2mm in length. The tears then flow through a horizontal segment of the canaliculus that is approximately 8mm in length. The angle between the vertical and horizontal segments of each lacrimal canaliculus is about 90 degrees. In most individuals, the horizontal segments of the canaliculus merge to form a common canaliculus that then leads to the lacrimal sac.

Punctal plugs are small plugs that can be inserted into the punctum. Punctal plugs were originally used to treat dry eye syndrome by blocking the outflow of tears from the eye and thus increasing the thickness of the tear film covering the eye. More recently, drug eluting punctal plugs have been proposed for use as drug delivery implants for treating certain conditions of the eye. For example, clinical studies have shown that substance eluting punctal plugs can be used to deliver doses of latanoprost, a prostaglandin analog, to the anterior segment of the human eye for the treatment of open angle glaucoma or hypertensive eyes. Journal of eye-net 10, page 23 of News Review, 2008 (EyeNet Magazine, News in Review).

Drugs for treating glaucoma and drugs for treating corneal disorders are most effective when delivered locally to the anterior surface of the eye.

Accordingly, there is a need in the art for improved punctal plugs that maximize the delivery of drugs and/or other substances to the corneal surface.

Disclosure of Invention

The present invention provides an implantable substance delivery device that is implantable in a punctum of an eye of a human or animal subject and that can be used to deliver therapeutic or diagnostic substance(s) to the eye or other areas of the body. In addition, the present invention provides methods of treating various conditions using the implantable substance delivery devices of the present invention.

According to one aspect of the present invention, there is provided a substance delivery device implantable in a punctum of an eye of a human or animal subject. These devices generally comprise (a) a punctal plug having a plug body and a substance insert-receiving cavity formed in the plug body, and (B) a substance insert consisting of or comprising a substance-eluting core having a distal end and a proximal end, wherein (C) the substance insert is positioned in the substance insert-receiving cavity of the punctal plug such that, when the device is implanted in a punctum of an eye, a first tear-eluting location at the proximal end of the substance-eluting core will be exposed to tears and/or other fluid(s) dispensed to the anterior surface of the eye such that the substance will elute from the first tear-eluting location into tears and/or other fluid(s) dispensed to the anterior surface of the eye, and at least one additional tear-eluting location on the substance-eluting core will also be exposed to tears and tears dispensed to the anterior surface of the eye And/or other fluid(s), such that the substance will elute from the at least one additional tear-eluting location into the tear fluid and/or other fluid(s) dispensed to the anterior surface of the eye. In some embodiments, one or more channels are formed to allow tears and/or other fluid(s) to flow into the region adjacent the substance core, thereby creating additional tear-eluting locations. In some embodiments that include such channel(s), all or part of the device may be formed of a resilient or flexible material that allows the channel(s) to flex or expand/contract in response to movement of facial muscles, thereby creating a pumping-like effect that facilitates movement (e.g., flipping over) of tears and/or other fluid(s) into and out of the channel(s). In some embodiments, a portion (e.g., the distal end) of the substance core can be made substantially impermeable to the substance such that little or no substance will pass through the portion of the substance core while the substance remains free to elute from the desired tear-eluting location. Also, in some embodiments, all or a portion of the punctal plug body can be made substantially impermeable to the substance to prevent or eliminate unwanted diffusion of the substance through the punctal plug while allowing the substance to elute from a desired tear-eluting location.

According to another aspect of the present invention, a method of using an implantable substance delivery device having the foregoing features is provided. In these methods, the substance delivery device is implanted in a punctum of an eye of a human or non-human animal subject for the delivery of a substance for the diagnosis or treatment of a disease or condition or for experimental purposes, such as the creation of an experimental animal model, wherein the implanted substance delivery device is used to administer a substance that produces a pathological condition for the purpose of laboratory research and/or testing for possible treatment. The devices and methods of the present invention are particularly suited for delivering substances to the anterior surface of the eye via tear fluid and/or other fluid(s) dispensed to the anterior surface of the eye. Thus, the devices and methods of the present invention may be particularly useful for treating diseases and conditions affecting the cornea, conjunctiva, sclera, anterior chamber angle, trabecular meshwork, schlemm's canal, manifolds emanating from schlemm's canal, or other anatomical structures in the eye into which a therapeutically effective amount of a substance administered topically to the anterior surface of the eye will be dispensed.

Other aspects, objects, applications, elements, details, and features of the present invention will be apparent to one of ordinary skill in the relevant art after reviewing the detailed description and examples set forth below.

Drawings

Figure 1 is a pictorial view of a human eye and associated lacrimal drainage system and a substance delivery device of the present invention implanted in the lower punctum or punctum.

Fig. 1A is an enlarged view of an area 1A of fig. 1.

Fig. 1B is an illustration of a tear film covering the cornea of the eye shown in fig. 1.

Fig. 2 is an exploded side view of a first embodiment of the substance delivery device of the present invention.

Fig. 2A is a perspective view of a fully assembled substance insert component of the substance delivery device of fig. 2.

Fig. 2B is a partial top view of the substance delivery device of fig. 2.

Fig. 3 is an exploded side view of a second embodiment of the substance delivery device of the present invention.

Fig. 3A is a perspective view of the fully assembled substance insert component of the substance delivery device of fig. 3.

Fig. 3B is a partial top view of the substance delivery device of fig. 3.

Fig. 4 is an exploded side view of a third embodiment of the substance delivery device of the present invention.

Fig. 4A is a top view of a punctal plug component of the substance delivery device of fig. 4.

Fig. 4B is a perspective view of the fully assembled substance insert component of the substance delivery device of fig. 4.

Fig. 4C is a partial top view of the substance delivery device of fig. 4.

Fig. 5 is an exploded side view of a fourth embodiment of the substance delivery device of the present invention.

Fig. 5A is a partial top view of the substance delivery device of fig. 5.

Fig. 6 is an exploded side view of a fifth embodiment of the substance delivery device of the present invention.

Fig. 6A is a partially exploded/partially assembled perspective view of a substance insert component of the substance delivery device of fig. 6.

Fig. 6B is a fully assembled perspective view of the substance insert components of the substance delivery device of fig. 6.

Fig. 7 is a side, partially cross-sectional view of an alternative punctal plug component that can be used in the substance delivery device of the invention, where a coating (shown partially cut away) is provided in the area of the punctal plug surrounding the substance insert to prevent or impede passage of substance through the portion of the punctal plug.

Fig. 8A through 8C are perspective views of alternative configurations of the punctal plug components of the substance delivery device of the invention.

Detailed Description

The following detailed description and the accompanying drawings, which are referred to, are intended to describe some, but not necessarily all, examples or embodiments of the invention. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The contents of the detailed description and the drawings are not intended to limit the scope of the invention in any way.

The entire disclosure of each of the following co-pending U.S. and PCT international patent applications is expressly incorporated herein by reference:

application serial number	Publication number	Date of filling	State of the country
				12/231,989	2009/0104248	9/8/2008	United states of America
12/231,986	2009/0104243	9/5/2008	United states of America
				13/378,710	2009/0264861	2 month and 17 days 2009	United states of America
12/463,279	2009/0280158	2009 5, 8 days	United states of America
				12/432,553	Is free of	4 and 29 months in 2009	United states of America
PCT/US2009/002611	WO 2009/134371	4 and 29 months in 2009	PCT
				12/231,986	2009/0104243	9/5/2008	United states of America

Defining: as used herein, the following words and/or phrases should be defined as follows:

the term "substance" includes diagnostic, therapeutic, nutritional and cosmetic substances such as, but not limited to: chemicals, drugs, therapeutic agents, diagnostic agents, biologicals, radioactive agents, contrast agents, dyes, lubricants and nutrients, including but not limited to those listed in any of the applications listed in the tables above and expressly incorporated herein by reference.

The term "subject" includes human and other animal subjects, including human and animal patients undergoing therapeutic, prophylactic and diagnostic treatment, as well as human or animal subjects to whom a particular substance has been administered for experimental purposes in order to study or observe the effect of the substance or to induce a disease or condition as in animal models for such disease or condition.

The term "other fluid(s)" includes a body fluid or fluids other than tears (e.g., interstitial or interstitial fluid, mucous secretions, lipid secretions, etc.) as well as fluids of exogenous origin (e.g., artificial tears, medicinal or non-medicinal eye drops, eye washes, lavages, etc.).

The drawings and the following detailed description and examples are intended to illustrate and describe some, but not necessarily all, examples or embodiments of the invention. The described examples and embodiments are to be considered in all respects as illustrative and not restrictive. The diagrams of fig. 2-6 should be considered exemplary with respect to the components of the devices and are not intended as illustrations of methods of making those devices. The contents of the detailed description and the drawings are not intended to limit the scope of the invention in any way.

Fig. 1 is a diagram of the human eye anatomy and associated lacrimal system. It is sufficient to focus on the latter, which consists of the upper and lower canaliculi, known as the upper and lower canaliculi UC and LC, and the lachrymal sac or LS, for the purposes of this discussion. The superior and inferior canaliculi UC, LC each terminate in an upper or superior punctal aperture UP and a lower or inferior punctal aperture LP, respectively. The punctal holes UP, LP are circular or slightly oval shaped holes that are about 0.3mm in size and are surrounded by a fairly dense, relatively avascular tissue connecting ring having a depth of about 1 mm. Each of the punctal apertures UP, LP leads to a generally vertical segment of the respective lacrimal canaliculus UC or LC. Each lacrimal canaliculus UC, LC is an approximately 0.5mm diameter tube of stratified squamous epithelial lining surrounded by elastic tissue that allows the lacrimal canaliculus to expand to approximately three times its normal size. Tears flow through the canaliculi UC and LC and into the lacrimal sac LS. Tears that accumulate in the lacrimal sac LS then drain from the lacrimal sac LS into the nasal cavity through the nasolacrimal duct NLD.

In fig. 1, one embodiment of a substance delivery device 10 of the present invention is implanted in the lower punctal orifice LP and lower canaliculus LC as shown.

Figure 1B shows a typical tear film TF on the anterior surface of the cornea C of a human eye. The tear film TF consists of three layers, namely an inner mucus layer ML, an outer lipid layer LL and an aqueous layer AL therebetween.

Fig. 2-2B show a first embodiment of the substance delivery device 10 of the present invention. In this embodiment, substance delivery device 10 includes a punctal plug component 12 and a substance insert component 11. Punctal plug 12 has an elongated body portion 18 and a substance insert receiving portion 20. The punctal plugs can be formed of any suitable non-biodegradable, partially biodegradable, or fully biodegradable material(s), such as the materials set forth in the above tables and in the applications expressly incorporated herein by reference. Examples of materials from which punctal plugs 12 can be formed include, but are not limited to, elastomers, silicones, hydrophilic polymers, hydrophilic silicones, polyurethanes, acrylics, polyvinyl alcohols, hydrogels, polyurethane hydrogels, solid hydrogels, silicone/polyurethane copolymers, silicone/polyethylene glycol copolymers, silicone/hydroxyethyl methacrylate copolymers (HCMA), and the like. A substance insert-receiving cavity 24 is formed within the substance insert-receiving portion 20 and the flange 22 optionally extends around the mouth or opening of the substance insert-receiving cavity 24. The substance insert 11 comprises a sheath 14 and a substance core 16. The substance core 16 of this embodiment, or any other embodiment described herein, includes a matrix material, such as a polymer or other suitable material, combined or loaded with a therapeutic or diagnostic substance. Specific matrix materials, therapeutic/diagnostic substances, and methods for making substance cores 16 are listed in the above tables and are fully described in the applications expressly incorporated herein by reference. One specific example of a material that may form the matrix of the substance core 16 is silicone elastomerBodies (e.g., Nusil MED6385, Nusil technology, Inc., Camptolty, Calif.). Sheath 14 has a lumen into which a substance core 16 is inserted. In this embodiment, the side wall of the sheath 14 is corrugated such that an elongated groove or channel 29 is formed in the outer surface of the sheath 14. The sheath 14 in this and other embodiments described below is formed of a material that is substantially impermeable to the substance, such as polyimide, polyethylene or polyethylene terephthalate (PET), but holes 28 are formed in the side walls of the sheath 14 along each channel 29. As seen in fig. 2A and 2B, the substance core is positioned within the lumen of the sheath 14 to form the substance insert 11. Substance insert 11 is then first inserted distally into substance insert-receiving cavity 24 of punctal plug 12. As seen in fig. 1 and 1A, the device 10 is inserted through the inferior or lower punctum LP such that the elongate body portion 18 of the punctal plug 12 is located in the horizontal portion of the inferior or lower lacrimal canaliculus LC and the substance insert receiving portion 20 is located within the vertical portion of the inferior or lower lacrimal canaliculus LC, with its flange 22 extending around the inferior or lower punctum hole LP. Tears and/or other fluid(s) may enter channel 29 and the substance may elute through pores 28 into tears and/or other fluid(s) that have entered channel 29. Moreover, the proximal end PE of the substance core 16 is exposed to tear fluid and/or other fluid(s) such that the drug also elutes from the proximal end of the substance core 16 into the tear fluid and/or other fluid(s) within the eye. Alternatively, the device may be constructed of a flexible material such that the channel 29 can flex (e.g., compress and decompress) in response to daily facial muscle movements (e.g., blinking eyes, opening and closing eyes, strabismus, etc.), thereby creating a pumping action that will move tears and/or other fluid(s) into and out of the channel, thereby increasing the turnover of tears and/or other fluid(s) within the channel and increasing the concentration of substances within the tear film TF and/or other fluid(s) covering the cornea C or the anterior surface of the eye. This may be accomplished by forming all or part of device 10 from material(s) that are sufficiently flexible to cause channel 29 to flex or compress and decompress in response to daily movement of facial muscles.Examples of such materials include, but are not limited to, silicone elastomers, hydrogels, and other elastomers, including hydrophilic polymers of the type commonly used in the construction of soft contact lenses. Also, optionally, all or part of the distal end of the substance insert 11 may be made substantially substance-impermeable so that the substance will not be lost through the distal end of the substance core 11. This may be achieved, for example, by placing a seal 17 (e.g., a substance-impermeable cap or coating) on the distal end PE of the substance core 16. In this embodiment or any other embodiment described herein, such a seal 17 may be formed from a cyanoacrylate (e.g., a uv curable cyanoacrylate, such as Loctite^TM4305, henkel corporation, dusseldorf, germany) or other suitable material that is substantially impermeable to matter, such as parylene (a parylene polymer), a metal coating (e.g., a silver-based coating that also provides antimicrobial activity), polyimide, impermeable silicone, thermoplastics (e.g., polyurethane, polyvinyl chloride), Polytetrafluoroethylene (PTFE), or other micro-permeable polymers.

In fig. 2-2B, sheath 14 is shown with a corrugated sidewall such that the lumen wall has a groove and an outer wall surface. In this embodiment, the substance core 16 may be extruded, die cut, press formed or otherwise shaped into a corresponding shape (e.g., the shape of a star) such that when inserted into the sheath 14, the substance core will substantially fill the lumen of the sheath, as seen in the figures. It will be appreciated, however, that alternative modes of constructing the sheath 14 are possible. For example, the longitudinal groove may be extruded or cut only in the outer surface of the sheath 14 and its lumen may have a circular, non-grooved inner wall. In such an alternative embodiment, a substance wick 16 having a simple cylindrical shape may be inserted into the lumen of sheath 14 so as to substantially fill the lumen.

The device 10, as well as the components of the other embodiments 10a, 10b, 10c, and 10d described herein, may be formed of any suitable material. In some embodiments, the device may be biodegradable. In other embodiments, it may be non-biodegradable. Examples of materials that may be used to construct punctal plugs 12, sheaths 14 and substance cores 16, as well as specific drugs and other substances that may be included in substance cores 16, are listed in the above tables and described in the applications expressly incorporated herein by reference.

Fig. 3-3B show a second embodiment of a substance delivery device 10a of the present invention. In this embodiment, the punctal plug member 12 is the same as the punctal plug member shown in fig. 2 and described above. However, in this embodiment, substance insert 11a comprises a combination of a sheath 30 (e.g., a tube) having a circular lumen wall and a cylindrical substance core 16 a. As described above with respect to the substance core 16 of the first embodiment, the substance core 16a may comprise a polymeric matrix (e.g., a silicone elastomer) combined with or loaded with a therapeutic or diagnostic substance. The longitudinal channel 32 in the form of a rectangular groove is cut (e.g., laser cut), extruded, or otherwise formed only in the outer surface of the sheath 30, allowing the lumen wall of the sheath to remain generally circular in cross-section. Sheath 30 is formed of a substantially substance-impermeable material (e.g., polyimide, polyethylene, PET, etc.). A bore 34 is formed through the wall of the sheath 30 within each longitudinal passage 32. As seen in fig. 3A and 3B, a cylindrical substance core 16a is inserted into the circular lumen of sheath 30 to form substance insert 11 a. Substance insert 11a is then first inserted distally into substance insert-receiving cavity 24 of punctal plug 12. In the same manner as in fig. 1 and 1A, the device 10a can be inserted through the inferior or lower punctum LP such that the elongate body portion 18 of the punctal plug 12 is located in the horizontal portion of the inferior or lower lacrimal canaliculus LC and the substance insert receiving portion 20 is located within the vertical portion of the inferior or lower lacrimal canaliculus LC with its flange 22 extending around the inferior or lower punctal aperture LP. Tears and/or other fluid(s) may then enter the channel 32 and the substance may elute through the pores 34 into tears and/or other fluid(s) that have entered the channel 32. Also, as in the other embodiments, the proximal end PE of the substance core 16a is uncovered and exposed to tears and/or other fluid(s) so that the drug can also elute from the proximal end of the substance core 16a into the tears and/or other fluid(s) in the eye. Alternatively, the device may be constructed of a flexible material such that the channel 32 may flex (e.g., compress and decompress) in response to daily facial muscle movements (e.g., blinking eyes, opening and closing eyes, strabismus, etc.), thereby creating a pumping action that will move tears and/or other fluid(s) into and out of the channel 32, thereby promoting inversion or exchange of tears and/or other fluid(s) within the channel and increasing the concentration of the substance within the tear film TF overlying the cornea C of the eye. Also, optionally, all or part of the distal end of the substance insert 11a may be substantially impermeable to the substance, such that the substance will not be lost through the distal end of the substance core 11 a. This may be achieved, for example, by the presence of an optional seal 17 (e.g., a substantially impermeable cap or coating) as described above on the distal end DE of the substance core 16 a.

Fig. 4-4C show a third embodiment of a substance delivery device 10b of the present invention. In this device 10b, punctal plug 12a differs from punctal plug 12 used in the embodiment of fig. 2 and 3 in that substance insert receiving portion 20a has a substance insert-receiving cavity 24a that is polygonal in cross-section rather than circular in cross-section. Substance insert 11b includes a cylindrical substance-impermeable sheath 40 having a bore 42 formed through a sidewall thereof and a cylindrical substance insert 16a positioned within the cylindrical sheath 40. As described above, a seal 17 (e.g., a substance-impermeable cap or substance-impermeable coating) may optionally be provided on the distal end DE of substance insert 16a to prevent elution of the substance through the distal end DE of substance insert 16 a. As seen in fig. 4C, when the cylindrical substance insert 11b is inserted into the polygonal substance insert-receiving cavity 24a, the channel 27 will remain open so that tears and/or other fluid(s) can flow into the channel 27. The apertures 42 are preferably arranged in rows and the substance insert 11b is rotatably oriented within the substance insert-receiving cavity 24a such that the rows of apertures 42 are positioned adjacent the channels 27 such that the substance from the substance core 16a can elute through the apertures into tear fluid and/or other fluid(s) entering the channels 27. To facilitate such precise rotational orientation of substance insert 11b to align apertures 42 with channels 27, indicia 41 may be provided on the proximal end of substance insert 11a to indicate the location of some or all of rows of apertures 42. Such indicia 41 may then be used during assembly of the device to ensure that the aperture 42 is positioned adjacent the channel 27, thereby facilitating elution of the substance to tears and/or other fluid(s) within the channel 27. As in other embodiments, some or all of the walls of the substance insert-receiving portion 20a of the punctal plug 12a can be constructed of a flexible material as described above to allow the walls of the channel 27 to flex (e.g., compress and decompress) in response to daily facial muscle movements (e.g., blinking, eye opening and closing, strabismus, etc.), thereby creating a pumping action that will move tears and/or other fluid(s) into and out of the channel 27, thus increasing the turnover or exchange of tears and/or other fluid(s) within the channel and increasing the concentration of the substance within the tear film TF that covers the cornea C of the eye. Moreover, it will be appreciated that various alternative designs of this embodiment may be devices in which, rather than being polygonal in cross-section, the walls of the substance insert-receiving cavity 24a may be ribbed, grooved, oval, or otherwise provided with surface breaks, spacers, or struts such that one or more channels or gaps will exist between the outer surface of the substance insert 11b and the inner side walls of the substance insert-receiving cavity 24 a.

In some applications, the sheath portion 14, 30, 40 of the substance insert 11, 11a, 11b described above may be omitted and the substance insert 11, 11a, 11b may be composed of, or substantially consist of, the substance core 16, 16a alone. In some such embodiments, a desired groove, depression, or other channel may be cut or directly formed in the outer surface of the substance core 16, 16a or in the adjacent inner wall of the substance insert-receiving cavity 24, 24a of the punctal plug 12, 12 a. This concept is illustrated in a fourth embodiment of a substance delivery device 10c shown in fig. 5-5A. In this embodiment, the punctal plug 12a of fig. 4 is used in conjunction with a substance insert 11c consisting of only substance core 16a without any surrounding sheath. As noted above, a seal 17 (e.g., a substance-impermeable cap or substance-impermeable coating) may optionally be provided on the distal end DE of substance core 16a to prevent elution of the substance through the distal end DE of substance core 16 a. As seen in figure 5A, when the cylindrical substance core 16a is inserted into the polygonal substance insert-receiving cavity 24a, the channel 27 will remain open so that tears and/or other fluid(s) can flow into the channel 27 and the drug from the unsheathed substance core 16a can elute into the tears and/or other fluid(s) entering the channel 27.

In some embodiments, the substance insert may comprise a plurality of sheaths, tear fluid(s) and/or fluid flow channel(s) formed between the sheaths. For example, FIGS. 6-6B illustrate a fifth embodiment of a substance delivery device 10d of the present invention. In this device 10d, punctal plug 12 is the same as the punctal plug shown in fig. 2 and 3 and described above, and substance insert 11d includes a substance core 16b that is square in cross-section, an inner sheath 50 that is square in cross-section, and an outer sheath 54 that is circular in cross-section. The substance core 16b is formed of a matrix material that is combined or loaded with a desired therapeutic or diagnostic substance, as described above with respect to the substance cores 16, 16a of the other embodiments. The inner and outer sheaths 50, 54 are formed of material(s) that are substantially impermeable to matter, such as polyimide. An aperture 52 is formed in the sidewall of the inner sheath 50 as shown. The substance core 16b is disposed within and substantially fills the lumen of the inner sheath 50. The inner sheath 50 (with the substance core 16b positioned therein) is inserted into the lumen of the outer sheath 54, thereby forming the substance insert 11d for this embodiment. Because the inner sheath 50 is square in cross-section and the outer sheath 54 is circular in cross-section, an open channel 56 extends along the sides of the inner sheath 50 between the outer surface of the inner sheath 50 and the inner lumen surface of the outer sheath 54. Substance insert 11d is inserted into substance insert-receiving cavity 24 of punctal plug 12. The proximal end PE of the substance core 16b remains exposed so that when implanted in the punctum, the substance can elute from the proximal end of the substance core 16b into the tear fluid and/or other fluid(s) accumulated in the area of the punctum. Additionally, when so implanted, tears and/or other fluid(s) can enter the channel 56 and the substance can elute from the substance core 16b through the pores 52 into tears and/or other fluid(s) that have entered the channel 56. As described above with respect to other embodiments, some or all of the walls of the substance insert receiving portion 20 of the punctal plug 12, some or all of the outer sheath 54, and/or some or all of the inner sheath 50 can be constructed of a flexible material to allow the walls of the channel 56 to flex (e.g., compress and decompress) in response to daily facial muscle movements (e.g., blinking, eye opening and closing, strabismus, etc.), thereby creating a pumping action that will move tear fluid and/or other fluid(s) into and out of the channel 56. Such inversion or exchange of tears and/or other fluid(s) within the channel will result in a greater concentration of the substance within the tear film TF overlying the cornea C of the eye.

In applications where it is desired to deliver therapeutic or diagnostic substances to or through the cornea or eye, it is desirable to dissolve the substance in the tear film TF overlying the cornea of the eye while preventing or minimizing accidental loss of the substance by other routes, such as by absorption directly into the tissue surrounding the punctum and/or canaliculus LC in which the device is implanted (hereinafter often referred to as "perilacrimal" tissue absorption) or by excretion into the nose via the nasolacrimal system. One way to limit or prevent such loss of material is to make all or part of the punctal plug 12, 12a material impermeable so that the material cannot diffuse or pass through the wall of the punctal plug 12, 12 a. This may be particularly important in embodiments where the punctal plugs 12, 12a are formed of silicone or other materials through which substances may pass. In this regard, fig. 7 shows an improved punctal plug 12b having an elongated body portion 18 and a substance insert receiving portion 20 b. The substance insert receiving portion 20b may have the same configuration as any of the substance insert receiving portions 20, 20a described above. However, in this embodiment, the coating 60 has been applied to the outer surface of the side wall of the substance insert receiving portion 20 b. Such coatings can also be applied to other portions of the punctal plug 12b or to the entire punctal plug 12 b. The coating 60 is a material that is impermeable to any substance that will elute from a substance insert positioned within the substance insert receiving portion 20b of the punctal plug. This will prevent the passage of material through the sidewall of material insert receiving portion 20b (or any other portion of punctal plug 12b on which coating 60 is present). In applications where such a mode of material absorption/loss is not required, the presence of the coating 60 can limit the ability to absorb or otherwise absorb the substanceThe possibility of the substance being absorbed by the tissues surrounding the lacrimal canaliculus or excreted through the nasolacrimal system. The coating 60 can also maximize the amount of material that is dispersed or dissolved in the tear film TF and thus delivered to the anterior surface of the eye via the tear film. In particular, applicants have determined that in embodiments where the punctal plug 12b is formed of silicone and the substance insert comprises latanoprost for the treatment of glaucoma, some of the latanoprost will diffuse or pass through the wall of the punctal plug 12 and thus may be absorbed by the peri-lacrimal tissue or lost through drainage of the nasolacrimal system. This is problematic because latanoprost is most effective for the treatment of glaucoma when delivered locally to the cornea of the eye so that it is absorbed through the cornea into the anterior chamber of the eye. However, when the substance impermeable coating 60 is applied to the outer surface of the substance insert receiving portion 20b and/or other portions of the punctal plug 12b, the loss of latanoprost by diffusion or through the punctal plug 12b is significantly prevented. Such a coating 60 may be formed of any suitable material, such as a cyanoacrylate (e.g., a UV curable cyanoacrylate, such as Loctite)^TM4305, Henkel Corporation, dusseldorf, germany) or other suitable material that is substantially impermeable to matter, such as parylene (a parylene polymer), a metal coating (e.g., a silver-based coating that also provides antimicrobial activity), polyimide, non-permeable silicone, thermoplastics (e.g., polyurethane, polyvinyl chloride), Polytetrafluoroethylene (PTFE), or other micro-permeable polymers.

The embodiments of the invention described above utilize a substantially "L" shaped punctal plug 12, 12a, 12b, with an elongated body portion 19 extending at right angles to a substance insert receiving portion 20, 20a, 20 b. It should be appreciated, however, that the present invention may also be used in conjunction with any other punctal plug configurations and designs, many of which do not extend into the horizontal portion of the lacrimal canaliculus LC. Examples of some alternative punctal plugs 12C, 12d, and 12e that may be used in place of those described above are shown in fig. 8A, 8B, and 8C, as well as in other figures disclosed in the patent applications listed above and expressly incorporated herein by reference.

The devices and methods of the present invention can be used to treat a wide variety of conditions, as described in detail in the applications listed in the tables above and expressly incorporated herein by reference. In particular, the devices and methods of the present invention can be used to deliver a desired substance(s) to the anterior surface of the eye to treat an ocular condition that affects the cornea, conjunctiva, sclera, anterior chamber, trabecular meshwork, schlemm's canal, the manifold emanating from schlemm's canal, or other anatomical structures (e.g., structures of the anterior segment) into which a therapeutically effective amount of the substance administered locally to the anterior surface of the eye will be dispensed. Non-limiting examples of ocular conditions that may be treated by therapeutic substances delivered using the devices and methods of the present invention include glaucoma, hypertensive eye, corneal conditions, dry eye, allergy, infection, inflammation, and pain.

It should also be appreciated that the invention has been described above with reference to certain examples or embodiments of the invention, but that various additions, deletions, alterations and modifications may be made to those examples or embodiments without departing from the intended spirit and scope of the invention. For example, any element or attribute of one embodiment or example may be included or used in another embodiment or example, unless otherwise indicated as such would render the embodiment or example unsuitable for its intended use. Moreover, where steps of a method or process are described or listed in a particular order, the order of such steps may be changed unless otherwise indicated as such would render the method or process unsuitable for its intended purpose. All reasonable additions, deletions, modifications and alterations should be considered equivalents of the described examples and embodiments and should be included within the scope of the following claims.

Claims (43)

1. A substance delivery device implantable in a punctum of an eye of a human or animal subject, the device comprising:

a punctal plug comprising a plug body and a substance insert-receiving cavity formed in the plug body;

a substance insert consisting of or comprising a substance eluting core having a distal end and a proximal end;

the substance insert is positioned in the substance insert-receiving cavity of the punctal plug such that when the device is implanted in a punctum of an eye,

a) a first tear-eluting location proximal to the substance-eluting core will be exposed to tears and/or other fluid(s) dispensed to the anterior surface of the eye such that the substance will elute from the first tear-eluting location into tears and/or other fluid(s) dispensed to the anterior surface of the eye; and is

b) At least one additional tear-eluting location on the substance-eluting core will also be exposed to tears and/or other fluid(s) dispensed to the anterior surface of the eye, such that the substance will elute from the at least one additional tear-eluting location into tears and/or other fluid(s) dispensed to the anterior surface of the eye.

2. A device according to claim 1 wherein the first tear-eluting location comprises the entire proximal end of the substance eluting core.

3. A device according to claim 1 or 2, wherein at least a portion of the distal end of the substance eluting core is impermeable to the substance such that the substance is substantially prevented from eluting from the distal end of the substance eluting core.

4. A device according to claim 1 wherein the substance insert-receiving cavity has at least one sidewall and wherein the substance insert and the cavity sidewall are configured relative to each other such that, when the substance insert is inserted into the cavity, at least one channel is formed into which tears and/or other fluid(s) dispensed to the anterior surface of the eye can enter, and wherein the at least one additional tear-eluting location on the substance eluting core is located adjacent to the at least one channel.

5. A device according to claim 1 wherein at least one channel is formed in a side of the substance insert such that tears and/or other fluid(s) can enter the channel, and wherein the at least one additional tear-eluting location on the substance eluting core is located adjacent the at least one channel.

6. A device according to claim 1 wherein at least one channel is formed in a side wall of the substance insert-receiving cavity such that tears and/or other fluid(s) can enter the channel, and wherein the at least one additional tear-eluting location on the substance eluting core is located adjacent the at least one channel.

7. The device of claim 1, wherein the substance eluting core comprises a polymer matrix to which a quantity of a substance is bound.

8. The device of claim 7, wherein the polymer matrix comprises silicone.

9. A device according to claim 3 wherein a seal is located on the distal end of the substance eluting core.

10. The device of claim 9, wherein the sealant comprises a quantity of sealant or adhesive material.

11. The device of claim 10, wherein the sealant or adhesive material comprises ethyl cyanoacrylate.

12. The device of claim 1, wherein the substance insert consists essentially of the substance eluting core.

13. The device of claim 1, wherein the substance insert consists of the substance eluting core.

14. The device of claim 1, wherein the substance insert comprises a combination of the substance eluting core and a sheath element.

15. The device of claim 14, wherein the sheath member has a sidewall, a lumen, an open proximal end, and a distal end, and wherein the substance eluting core is disposed in the lumen of the sheath member.

16. The device of claim 15, wherein at least a portion of the sheath member is formed of a material that is substantially impermeable to the substance such that the substance is substantially prevented from eluting through the at least a portion of the sheath member.

17. The device of claim 16, wherein the sheath member is formed of at least one material selected from the group consisting of polyimide, polyethylene, and polyethylene terephthalate.

18. The device of claim 16, wherein the entire sheath member is formed of a material that is substantially impermeable to the substance such that the substance is substantially prevented from eluting through the sheath member.

19. A device according to any one of claims 14, 15, 16, 17 or 18 wherein there is at least one channel to allow tear fluid and/or other fluid(s) to flow adjacent the sheath member and wherein the at least one additional tear-eluting location comprises one or more apertures formed in the sheath member adjacent the at least one channel such that the substance will elute from the substance-eluting core, through the one or more apertures, into tear fluid and/or other fluid(s) that have entered the at least one channel.

20. The device of claim 19, wherein the one or more holes comprise a plurality of holes arranged in rows.

21. The device of claim 20, wherein the substance insert further comprises at least one marker operable to facilitate positioning of the substance insert within the substance insert-receiving cavity such that the row of apertures is positioned adjacent to the channel.

22. The device of claim 19, wherein each aperture has a diameter or maximum cross-sectional dimension of from about 0.001mm to about 0.5 mm.

23. The device of claim 19, wherein the at least one channel comprises at least one groove or elongated depression formed in the sheath element.

24. The device of claim 19, wherein a sidewall of the substance insert-receiving cavity is configured to create the at least one channel.

25. The device of claim 24, wherein the substance insert-receiving cavity is polygonal in cross-section.

26. The device of claim 1, wherein the substance insert comprises:

an outer sheath element comprising a sidewall, a lumen, an open proximal end, and a distal end;

an inner sheath member comprising a sidewall, a lumen, an open proximal end, and a distal end; and is

Wherein the substance core is disposed in the lumen of the inner sheath member.

27. A device according to claim 26 wherein the inner sheath member and the outer sheath member are configured relative to one another such that at least one channel into which tears and/or other fluid(s) may flow exists between the side wall of the inner sheath member and the side wall of the outer sheath member, and wherein the at least one additional tear-eluting location comprises one or more apertures formed in the inner sheath member adjacent the at least one channel to allow the substance to elute from the substance core, through the at least one aperture, into tears and/or other fluid(s) that have entered the at least one channel.

28. A device according to any one of claims 4, 5, 6, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27, wherein the at least one channel flexes due to specific muscle movements, thereby causing tears and/or other fluid(s) to move into and out of the at least one channel.

29. The device of claim 28, wherein flexing of the at least one channel results from at least one muscle movement selected from the group consisting of: eye closure, blinking and strabismus.

30. The device of claim 1 or 28, wherein the plug body is formed of at least one material selected from the group consisting of: elastomers, silicones, hydrophilic polymers, hydrophilic silicones, polyurethanes, acrylics, polyvinyl alcohols, hydrogels, polyurethane hydrogels, solid hydrogels, silicone/polyurethane copolymers, silicone/polyethylene glycol copolymers, silicone/hydroxyethyl methacrylate copolymers (HCMAs), and any one or more combinations thereof.

31. The device of claim 1, wherein at least a portion of the plug body positioned adjacent to the substance insert-receiving cavity is impermeable to the substance, thereby preventing the substance from eluting through the portion of the plug body.

32. The device of claim 31, wherein the entire plug body is substantially impermeable to the substance.

33. The device of claim 31, wherein the at least a portion of the plug body is made impermeable to the substance by a coating impermeable to the substance.

34. The device of claim 33, wherein the coating material is selected from the group consisting of: cyanoacrylates, ultraviolet curable cyanoacrylates, parylene (parylene polymer), metal coatings, silver-based coatings, polyimides, non-permeable silicones, thermoplastics, polyurethanes, polyvinyl chloride, Polytetrafluoroethylene (PTFE), and any one or more combinations thereof.

35. The device of claim 31, wherein the at least a portion of the plug body is formed from a combination of a polymer and a material that renders it impermeable to the substance.

36. The device of claim 1, wherein the therapeutic substance comprises a substance effective to treat an eye condition.

37. The device of claim 36, wherein the device delivers a therapeutically effective amount of a substance to treat an ocular disorder affecting the cornea, conjunctiva, sclera, anterior chamber, trabecular meshwork, schlemm's canal, a collecting canal emanating from schlemm's canal, or other anatomical structures in the eye to which a therapeutically effective amount of a substance administered topically to the anterior surface of the eye will be dispensed.

38. The device of claim 37, wherein the device delivers a therapeutically effective amount of a substance to treat a condition selected from the group consisting of: glaucoma, ocular hypertension, corneal disorders, dry eye, allergy, infection, inflammation and pain.

39. The device of claim 38, wherein the device delivers a therapeutically effective amount of a substance to treat glaucoma or hypertensive eye, and wherein the substance is selected from the group consisting of: beta adrenergic antagonists, alpha adrenergic agonists, prostaglandin analogs, parasympathomimetics, and carbonic anhydrase inhibitors.

40. The device of claim 39, wherein the therapeutic substance is selected from the group consisting of: latanoprost, travoprost and bimatoprost.

41. A method for treating a condition of the eye in a human or non-human animal subject, the method comprising the steps of:

(A) obtaining a substance delivery device according to any of claims 1-40, wherein the substance core elutes a substance effective to treat the condition;

(B) implanting the substance delivery device in a punctum of an eye of the subject such that the substance elutes from the substance core into tear fluid and/or one or more other fluids that are distributed to the anterior surface of the eye at a concentration that results in a therapeutically effective dose of the substance being delivered to or through the cornea of the eye.

42. The method of claim 41 wherein the condition is glaucoma and wherein the substance is a substance effective to treat glaucoma and wherein step B results in transcorneal delivery of a therapeutically effective amount of the substance into the anterior chamber of the eye.

43. The method of claim 42, wherein said delivering is for at least about 90 days.